Emerging evidence indicates that a crucial post-translational lysine deacetylation has been identified as an important regulator of gene expression as well as enzyme activities that are involved in various biological functions, including mitochondrial function. Sirtuins (SIRTs) are NAD+-dependent protein deacetylases that mediate this post-translational modification by removing the acetyl groups from a wide range of proteins that have been demonstrated to be important in longevity pathways, DNA repair, antioxidant enzyme activity, and control of metabolic enzymes.
Seven members of the SIRT family have been identified in mammals. All share the same highly conserved NAD+-binding site and a Sir2 catalytic core domain with variable amino and carboxyl residues. SIRT1-3 and SIRT5-7 catalyze NAD+-dependent substrate-specific protein deacetylation, whereas SIRT4 acts as a NAD+-dependent mono-ADP-ribosyltransferase. SIRT6 has both deacetylase and auto-ADP-ribosyltransferase properties.
Annexin-A1 (ANXA1), a 37 kDa protein, is a member of the annexin superfamily, which includes 13 calcium and phospholipid binding proteins with a significant degree of biological and structural homology (40-60%). ANXA1, originally identified as a mediator of the anti-inflammatory effects of glucocorticoids, has diverse biological functions including the regulation of inflammatory pathways, cell proliferation machinery, cell death signaling, and the process of carcinogenesis. Altering the expression or the localization of this protein can contribute to the pathogenesis of human diseases including inflammatory diseases, cardiovascular diseases and cancer.
It is an object of the present invention to provide new compositions comprising ANXA1 peptides, and methods of using such compositions, to treat diseases and disorders associated with reduced and/or aberrant SIRT amount and/or activity.